Letrozole (Femara)

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Letrozole (INN, trade name Femara) is an oral non-steroidal aromatase inhibitor for the treatment of hormonally-responsive breast cancer after surgery.
Estrogens are produced by the conversion of androgens through the activity of the aromatase enzyme. Estrogens then bind to an estrogen receptor, which causes cells to divide.
Letrozole prevents the aromatase from producing estrogens by competitive, reversible binding to the heme of its cytochrome P450 unit. The action is specific, and letrozole does not reduce production of mineralo- or corticosteroids.
In contrast, tamoxifen interferes with the estrogen receptor. Tamoxifen is also used to treat hormonally- responsive breast cancer. However, letrozole is effective only in post-menopausal women, in whom estrogen is produced predominantly by the adrenal glands. In pre-menopausal women, estrogen is produced in the ovaries, and letrozole is ineffective.
In the BIG 1-98 Study, of post-menopausal women with hormonally-responsive breast cancer, letrozole improved the recurrence of cancer, but not survival, compared to tamoxifen.
The retail price of Femara in the United States is approximately $1,015 per month.

Letrozole
Identifiers
CAS number 112809-51-5
ATC code L02BG04
PubChem CID 3902
DrugBank APRD01066
ChemSpider 3765

Chemical data
Formula C17H11N5
Mol. mass 285.303 g/mol
SMILES eMolecules & PubChem

Pharmacokinetic data
Bioavailability 99.9%
Protein binding 60%, mainly to albumin
Half-life 2 days

Therapeutic considerations
Pregnancy cat. ?
Legal status ? (CA)
FDA-approved use
Letrozole is approved by the United States Food and Drug Administration (FDA) for the treatment of local or metastatic breast cancer that is hormone receptor positive or has an unknown receptor status in postmenopausal women. Side effects include signs and symptoms of hypoestrogenism. There is concern that long term use may lead to osteoporosis, which is why prescriptions of Letrozole are often accompanied by prescriptions of osteoporosis-fighting medications such as bisphosphonates.
Off-label use
Letrozole has been used for ovarian stimulation by fertility doctors since 2001—having less side-effects than Clomiphene Citrate (Clomid) and less chance of multiple gestation. A Canadian study presented at the American Society of Reproductive Medicine 2005 Conference suggests that Letrozole may increase the risk of birth defects. A more detailed ovulation induction follow-up study found that Letrozole, compared with a control group of Clomiphene Citrate, had significantly lower congenital malformations and chromosomal abnormalities at an overall rate of 2.4% (1.2% major malformations) compared with Clomiphene Citrates 4.8% (3.0% major malformations). However, the use of Letrozole is not intended for ovulation induction, and the manufacturer, Novartis, has issued letters to doctors in Canada and the United States reiterating that it is not approved for such a use and is not safe to use with pregnant women or women who may become pregnant.
The anti-estrogen action of Letrozole is preferred by athletes and bodybuilders for use during a steroid cycle to reduce bloating due to excess water retention and prevent the formation of gynecomastia related breast tissue that is a side effect of some anabolic steroids.
Some studies have shown that Letrozole can be used to promote spermatogenesis in male patients suffering from nonobstructive azoospermia.
Letrozole has also been shown to delay the fusing of the growth plates in mice. When used with growth hormone, Letrozole has been shown thereputic for adolescents and children with short stature.
A related agent is anastrozole.
Letrozole has also been used to treat endometriosis.
Chemistry